Although many previous studies (1-11) have reported findings in
bioprosthetic heart valves, very few have focused on right-sided valves.
Herein, we report a series of pulmonary-site tissue valves explanted
between January 1995 and June 2003, with an emphasis on morphologic
findings.

The Toronto General Hospital and Toronto's Hospital for Sick
Children have a long history of pulmonary valve replacement surgery for
congenital heart disease, with a total of 1081 patients receiving 1335
pulmonary valve implants (including valves in conduits), as allografts
or bioprostheses. There were 514 living, adult patients (age >18
years) who underwent valve replacement from January 1995 to June 2003 at
these facilities. Fifty-four (10.5%) of these adults required
reoperation and valve replacement because of failed prosthetic valves.
Forty (74.1%) of the explanted valves were bioprostheses, and 14 (25.9%)
were allografts.

MATERIALS AND METHODS

Data were obtained by review of pathologic, clinical, and surgical
records. All pulmonary valve bioprostheses explanted from January 1995
to June 2003 at Toronto General Hospital have been included in the
current study. Most of these prosthetic heart valves had not been
treated with antimineralization agents.

All explanted prostheses were examined radiologically, grossly and
histologically, by one author (J.B.). The biologic parts of the valves
were removed from the superstructure (plastic-metal-fabric framework)
and decalcified. Sections were then submitted for histologic processing.
Paraffin-embedded sections were cut at 4 to 5 [micro]m and stained with
hematoxylin-eosin. A Movat pentachrome stain (for collagen and elastic
tissue) was obtained. Additional sections for microorganisms (Gram stain
and Gomori methenamine silver) were obtained if infective endocarditis
was suspected. Histologic examination was performed to document the
severity and location (cusps and/or porcine aorta) of pannus,
calcification, thrombus, inflammation, and tissue degeneration. The
sections were examined using a Leica DMRB microscope (Leica Systems,
Toronto, Ontario, Canada), and photomicrographs were obtained using a
Leica digital camera (DC 500, Leica).

Cusp tears were classified according to Ishihara et al. (12) Type I
tears involved the free edges of the cusps. Type II lesions were linear
perforations along the base of the cusps parallel to the sewing ring.
Type III lesions were large perforations in the center of the cusps, and
type IV lesions were pinholelike perforations in the cusps.

Host-tissue overgrowth, or pannus, was classified according to
Butany et al. (13) In this system, pannus covering part of the
circumference of the valve sewing ring was classified as mild. Pannus
covering the whole width of the ring and up to 2 mm of the cuspal tissue
was considered moderate, and severe pannus was indicated with coverage
of greater than 2 mm of the basal portion of a valve cusp.

[FIGURE 1 OMITTED]

Fisher exact test was used for contingency analysis of categoric
variables. Student t test was used for analysis of continuous variables.
All statistical tests were performed at a significance level of P <
.05.

RESULTS

The 40 bioprosthetic valves were explanted from 19 (47.5%) women
and 21 (52.5%) men. They were implanted for a mean of 14.3 [+ or -] 5.2
years (range, 2 to 26 years). The average patient age at the time of
valve implantation was 16.7 [+ or -] 10.3 years (range, 3 months to 53
years). For many patients, the explanted valve was not their first
prosthetic valve in that position, and hence, the average age of
patients at the time of the first implant would be somewhat younger,
10.3 [+ or -] 8.0 years. For all cases, significant valvular dysfunction
was seen on echocardiography, before explantation.

The morphologic features associated with structural valve
deterioration (SVD) included collagen degeneration, calcification,
prolapse, increased cusp stiffness/cusp immobilization, fluid
insudation, fibrosis and cusp tears (Figures 2 through 4). A total of 39
(97.5%) of the valves showed evidence of SVD (97.5%). The only valve
that did not show evidence of SVD was a Hancock valve that had been in
place for 2 years (the shortest duration in this series) and was
explanted because of severe pannus-causing valvular stenosis. Evidence
of stenosis was found in all 40 (100.0%) of the cases. Valvular
incompetence was determined based on cusp tears and cusp immobilization.
In total, 28 (70.0%) of the valves were incompetent. The average implant
duration of incompetent valves was 13.2 [+ or -] 4.6 years, and the
average implant duration of nonincompetent valves was 16.8 [+ or -] 6.0
years. This difference was statistically significant (P = .04). Overall,
27 (67.5%) of the valves showed all 3: SVD, stenosis, and incompetence.
One valve in this series was explanted because of infective
endocarditis. This valve had been in place for 12 years, and also showed
SVD, stenosis and incompetence. Morphologic findings are summarized in
the Table.

Calcification

Calcification was present in 32 (80.0%) of the valves (Figure 3).
The calcification was severe and diffuse in 22 (55.0%) of the cases. In
2 (5.0%) of the cases, the calcification was so severe that it formed a
plate or platelike layer over the valve cusps. A third case showed areas
of both platelike and nodular calcification in separate areas.

Valves with calcification had been implanted for a mean of 14.7 [+
or -] 4.9 years (range, 7 to 26 years). Among the 9 (22.5%) prostheses
implanted for less than 10 years, calcification was severe and diffuse
in 3 (33.3%) of the cases, whereas among the 31 (77.5%) prostheses
implanted for more than 10 years, calcification was severe and diffuse
in 19 (61.3%) (P = .25).

[FIGURE 3 OMITTED]

Pannus

Pannus was present on 39 (97.5%) of the explanted specimens. The
one case where there was no evidence of pannus was a conduit in which
most of the cuspal tissue had been destroyed. Severe pannus was found on
35 (87.5%) of the specimens, often covering both the flow and non-flow
surfaces, with extensions to the free margins. Of the remaining valves,
1 (2.5%) demonstrated moderate pannus, 1 (2.5%) of the valves displayed
mild pannus, and 2 (5.0%) of the cases could not be categorized because
of partial destruction of cusp tissue.

Cusp Immobilization

Significant pannus led to valve cusps immobilization in 22 (55.0%)
of the specimens. All 3 cusps were immobilized in 17 (42.5%) of the
cases, and all 17 of these had calcification in addition to pannus. Nine
(52.9%) of these 17 specimens had all 3 cusps immobilized in a partially
open position. Pannus extending onto both the flow and non-flow cuspal
surfaces led to retraction of collagen and shortening of the cusp
(Figure 2). In 4 (10.0%) of the 40 cases, all 3 cusps were immobilized
in the fully open position. There were 2 (5.0%) of the cases with all 3
cusps immobilized in a closed position.

Tears

Tears were present in 18 (45.0%) of the valves. These valves were
in place for an average of 14.3 [+ or -] 4.3 years. Nine (22.5%) of the
valves showed multiple tears. Overall, there was one type III tear, with
the rest of the tears being type I. The type III tear was an oval
perforation at the center of one cusp of a Carpentier-Edwards porcine
valve, measuring 0.4 cm by 0.2 cm. This valve had been in place for 18
years and was heavily calcified, with all cusps immobilized in the open
position.

Infective Endocarditis

In 1 (2.5%) of the cases, the primary mode of valve failure was
infective endocarditis. The explanted device was a conduit with a
Carpentier-Edwards porcine bioprosthesis that had been in place for 12
years. Gram positive cocci were present in thrombi on the cusps. The
cuspal tissue was not calcified. The wall of the conduit was acutely
inflamed and showed signs of necrosis.

Other Changes

In 3 (7.5%) of the cases, structural deterioration was so severe
that little cuspal tissue remained at explantation. These valves were
implanted for 26, 19, and 9 years. At the time of bioprosthetic valve
explantation, these patients were 32, 25, and 24 years old,
respectively.

Evidence of thrombi (generally small) was discovered in 11 (27.5%)
of the explanted valves. These valves were implanted for 13.1 [+ or -]
4.6 years (range, 7 to 21 years). Cusp prolapse was present in 5 (12.5%)
of the cases, of which 2 also demonstrated calcification. In 3 (60.0%)
of the 5 cases, only one cusp was prolapsed. All of these valves had
tears. In 1 (20.0%) of the cases, 2 cusps were prolapsed, and there was
extensive calcification and pannus formation. All 3 cusps were prolapsed
in 1 (20.0%) of the cases, and this valve also showed broad pannus
formation and extensive calcification.

There was only one case of paravalvular leak. This valve was in
place for 13.5 years in a conduit. Two tears were present in this valve,
measuring 0.6 cm and 0.3 cm in length, respectively. Despite this
finding, there was no evidence of any calcification. The valve did
display evidence of thrombus and severe pannus.

[FIGURE 4 OMITTED]

Valve Type

In total, 24 (60.0%) of the valves were porcine aortic
(Hancock/Carpentier-Edwards) and 16 (40.0%) were bovine pericardial
(Ionescu-Shiley low-profile). The porcine bioprostheses were in place
15.3 [+ or -] 5.8 years, whereas the pericardial valves were in place
for 12.7 [+ or -] 3.6 years. Calcification was present in 20 (83.3%) of
the porcine valves as compared with 12 (75.0%) of the pericardial
valves; severe calcification was seen in 12 (50.0%) versus 10 (62.5%) of
the valves, respectively. Cusp immobilization was similar in both groups
as well, with 54.2% (n = 13) of the porcine valves having one cusp
immobilized versus 56.3% (n = 9) in the pericardial group. All 3 cases
of severe SVD causing cusp destruction were from porcine valves,
comprising 18.8% of the porcine group. Differences in the above
morphologic changes of porcine versus bovine pericardial valves did not
reach statistical significance.

Nineteen (47.5%) of the explanted pulmonary valves were in
conduits. These valves were in place for 15.9 [+ or -] 5.0 years. The
remaining 21 (52.5%) bioprostheses were orthotopic implants. The
orthotopic implants were in place for 12.8 [+ or -] 4.9 years. Pannus
was severe in 15 (78.9%) of the conduits, and mild in 1 (5.3%), whereas
the remaining 3 (15.8%) of the valves in conduits could not be assessed
because of extensive cusp destruction. In the orthotopically placed
series, pannus was severe in 20 (95.2%) of the 21 cases and moderate in
1 (4.8%). Evidence of pannus extending to, or near, the free margin was
found on 10 (52.6%) of the 19 valve conduits and 6 (28.6%) of the 21
orthotopically placed valves. Fourteen (73.7%) of the 19 valve conduits
were calcified compared with 18 (85.7%) of the 21 orthotopically placed
valves. Differences in morphologic features of valves from conduits
versus orthotopic implants did not demonstrate statistical significance.

Nineteen (47.5%) of the 40 patients were younger than 30 years at
the time of valve explantation. Fourteen (73.7%) of these 19 patients
had immobilization of all 3 valve cusps. In those older than 30 years of
age, 3 (14.3%) had immobilization of all 3 cusps, a statistically
significant difference (P < .001). In the younger age group, 11
(57.9%) of the explanted valves showed severe and diffuse calcification
as did 11 (52.4%) of the valves in the older age group. Eight (42.1% and
38.1%, respectively) of the valves from each age group showed evidence
of cusp tears. These differences did not reach statistical significance.

COMMENT

The 40 explanted valves in this series had a relatively long period
of bioprosthesis survival (14.3 [+ or -] 5.2 years) in a fairly young
patient population. Although left-sided valve explants ranged in
duration from 2.2 to 8.5 years in various older studies, (1-3,11,14) we
recently reported on a series of Carpentier-Edwards supraannular (Baxter
Healthcare Corporation, now Edwards Life Sciences) and Hancock-II
(Medtronic Heart Valve Division) porcine bioprostheses that were in
place for 13.9 [+ or -] 3.9 and 10.0 [+ or -] 5.1 years, respectively.
(13) In the current series of pulmonary explants, the lower pressure
load in the right side of the heart likely enhanced the survival of some
valves, as 8 (20.0%) of our valve explants were in place for 20 or more
years.

Infective endocarditis has been demonstrated as a significant cause
of failure in aortic and mitral valve bioprostheses. The occurrence of
infective endocarditis has been reported at a linearized rate of 0.6%
per patient-year in Carpentier-Edwards porcine valves in the aortic and
mitral positions. (15) However, endocarditis was the cause of valve
failure in only 1 (2.5%) of the valves in our study. In addition, the
only case of paravalvular leak in our patient group occurred in this
patient with infective endocarditis, consistent with the theory that
paravalvular leak often occurs as a complication of endocarditis. (10)
Paravalvular leaks may, in part, be caused by ventricular closing
pressures and are, therefore, more common on the left side.

We found pannus almost universally (97.5%) in our cases, with
severe pannus present in 87.5% of these explanted valves. These findings
are consistent with our recent study of porcine explants, in which
pannus was found in 93.9% of cases. (13) Exuberant pannus may be
worsened by the longevity of implants, the relatively young age of the
patient population, and the narrower right ventricular outflow tract
(especially in those with the tetralogy of Fallot) and may be
exacerbated by the differences in hemodynamics in the right versus the
left side of the heart. Indeed, in early term analysis of pulmonary
conduits, a susceptibility to obstruction from pannus formation, in
conjunction with the effects of SVD (such as calcification and
thrombosis), has been observed. (16) Furthermore, the thickness of
pannus has been reported to increase dramatically in valved conduits
compared with nonvalved conduits. (17) In a large-scale study of
children younger than 18 years of age, more than 90% of prosthetic
pulmonary valve re-replacements were due to stenosis. (18) In a separate
study of porcine-valved conduits for right ventricular outflow tract
reconstruction, a small patient group (n = 16) was found to have a 60%
prevalence of severe conduit stenosis at 9 years after implant. (19) A
relatively large bioprosthesis, when placed in a comparatively narrow
right ventricular outflow tract, likely allows greater tissue-prosthesis
contact and more rapid and extensive host-tissue overgrowth. Clearly,
the extent of host-tissue overgrowth in pulmonary-valved conduits and
orthotopic pulmonary implants is problematic. The exact impact of age
and hemodynamic differences compared with the left side is, however,
difficult to determine.

Another interesting finding in this series of explanted valves is
their low incidence of cusp tears, considering the longevity of the
valves and the high incidence of other features of structural
deterioration. In our previous series of porcine bioprosthesis, tears
were found in 76.1% of explants, compared with 45.0% in the current
series. In many cases, severe pannus entirely covered one or more cusps,
possibly providing a coating or sheath to the bioprosthesis cusps, thus
protecting it from collagen fiber damage that would normally cause
tearing. The lower incidence of tearing may also be related to decreased
pressures on the right side of the heart compared with the left.

Calcification was found in 80.0% of the pulmonary bioprostheses,
most often with severe deposits spread throughout the cuspal tissue. The
progression of calcific deposits has been shown to increase with length
of implantation. (1) Furthermore, calcification of bioprostheses has
been shown to be accelerated in patients younger than 20 years of age
(4) and to be less extensive in patients older than 35 years of age.
(20) The high degree and severity of calcification and
calcification-related changes seen in our study would, therefore, be
expected, considering the young patient group analyzed and the
relatively long duration of valve implant. Whether or not the lower
pressures in the right ventricular outflow tract have any impact on this
is difficult to determine. Our study also found a marked increase in
cusp immobilization, with a significant rate of cusp immobilization
involving all 3 cusps in patients younger than 30 years old at the time
of valve explantation. The high incidence of calcification, pannus, and
cusp immobilization would have led to clinically significant stenosis in
the majority of valves in this series.

CONCLUSION

We have presented data from an 8-year review of explanted pulmonary
site bioprostheses, implanted in a young population, mainly for
congenital heart disease. There were no statistically significant
differences in morphologic findings between different valve types
(porcine aortic vs. bovine pericardial). The explanted bioprostheses had
a high rate of severe calcification and pannus over-growth, and these
changes together led to valve orifice stenosis. Severe cusp
immobilization was also a frequent finding, with the immobilization of
all 3 cusps being more common in patients younger than 30 years of age
(at the time of explantation). The valves in our series were in place
for considerably long periods of time. Host-tissue overgrowth is a
significant problem with bioprosthetic valves, particularly pulmonary
site implants, and needs further evaluation.

From the Departments of Pathology and Cardiovascular Surgery,
Toronto General Hospital and University of Toronto (Messrs Soor and
Leong and Drs Butany and Shapero); and the Division of Cardiovascular
Surgery, The Hospital for Sick Children, University of Toronto (Dr
Williams), Toronto, Ontario. Dr Shapero is now with the Department of
Dermatology, University of British Columbia, Vancouver, British
Columbia.

The authors have no relevant financial interest in the products or
companies described in this article.